By correcting the structure of citrinalin B (revised stereocenters in red), chemists found supporting evidence for a common precursor for two bioactive compounds from fungi.

By correcting the structure of citrinalin B (revised stereocenters in red), chemists found supporting evidence for a common precursor for two bioactive compounds from fungi.

Chemists have yet to learn all of the molecule-making tactics of the family of fungi that makes penicillin. And as a research report shows, collaborative efforts to further unravel fungal biosynthetic pathways can help scientists find new antibacterial and antitumor agents (Nature 2014, DOI: 10.1038/nature13273).

Richmond Sarpong and his group at the University of California, Berkeley, had run into a structure elucidation problem along one of these biosynthetic pathways that left them scratching their heads and issuing a call for help. On the basis of work from other teams, they expected that the alkaloids citrinalin B and cyclopiamine B would be pseudoenantiomers—that is, nearly mirror images of one another, but not quite. Yet that’s not what the reported structures for the molecules indicated.

The Berkeley team proposed a new structure for citrinalin B and asked UC Davis computational chemist Dean J. Tantillo for backup. The calculations supported the idea that the originally reported structure of citrinalin B had been misassigned. Armed with that evidence, Sarpong’s lab collaborated with Yale University’s Scott J. Miller to carry out chemical syntheses that confirmed the revised structure.

“Most synthetic chemists would have stopped at this stage,” organic chemist John L. Wood of Baylor University writes in a Nature commentary. “Sarpong chose to take things further.”

With Roberto G. S. Berlinck of the University of São Paulo, in Brazil, the chemist who first isolated the citrinalin natural products, Sarpong’s team carried out additional biosynthesis studies. Those results support a long-held idea that citrinalin, cyclopiamine, and related molecules come from a precursor containing a bicyclo[2.2.2]diazaoctane. What’s more, they discovered a new molecule, citrinalin C, which they think may be such a precursor.

This work, Wood adds, “beautifully illustrates how natural products continue to inspire research in synthesis, and that these efforts can benefit greatly from collaboration.”